Christopher C. Conway

Interaction of chronic stress with serotonin transporter and catechol-O-methyltransferase polymorphisms in predicting youth depression

Background: Investigations of gene–environment interaction (G×E) in depression have implicated a polymorphism in the promoter region of the serotonin transporter gene (5‐HTTLPR) as a moderator of the stress–depression relationship. However, recent evidence for 5‐HTTLPR G×E in depression has been inconsistent. This study examined the moderating effect of the val158met polymorphism in the catechol‐O‐methyltransferase (COMT) gene on the strength of 5‐HTTLPR G×E. Methods: A community sample of youth (n=384) was genotyped for 5‐HTTLPR and COMT. A multi‐method, multi‐informant index of chronic family stress was derived from interviews and questionnaires administered at youth age 15. G×G×E was examined in relation to depression diagnoses between ages 15 and 20 and depressive symptoms at age 20. Results: Significant three‐way interactions were observed for both depressive symptoms and diagnoses, such that 5‐HTTLPR G×E occurred only in the context of COMT val158 allele homozygosity. For val158 homozygotes, the 5‐HTTLPR LL genotype exerted a protective effect in the face of stress. No genetic main effect or two‐way G×E was found for 5‐HTTLPR. Conclusions: Inconsistent 5‐HTTLPR G×E findings to date may be partly attributable to unmeasured epistatic effects between 5‐HTTLPR and COMT val158met. Identifying the conditions under which 5‐HTTLPR G×E is most likely to operate may allow depression prevention and treatment efforts to target youth at highest risk. Depression and Anxiety, 2010.

Childhood social withdrawal, interpersonal impairment, and young adult depression: A mediational model

Building on interpersonal theories of depression, the current study sought to explore whether early childhood social withdrawal serves as a risk factor for depressive symptoms and diagnoses in young adulthood. The researchers hypothesized that social impairment at age 15 would mediate the association between social withdrawal at age 5 and depression by age 20. This mediational model was tested in a community sample of 702 Australian youth followed from mother’s pregnancy to youth age 20. Structural equation modeling analyses found support for a model in which childhood social withdrawal predicted adolescent social impairment, which, in turn, predicted depression in young adulthood. Additionally, gender was found to moderate the relationship between adolescent social impairment and depression in early adulthood, with females exhibiting a stronger association between social functioning and depression at the symptom and diagnostic level. This study illuminates one potential pathway from early developing social difficulties to later depressive symptoms and disorders.

Sensitizing effect of early adversity on depressive reactions to later proximal stress: Moderation by polymorphisms in serotonin transporter and corticotropin releasing hormone receptor genes in a 20-year longitudinal study

Previous research supports gene-environment interactions for polymorphisms in the corticotropin hormone receptor 1 gene (CRHR1) and the serotonin transporter gene linked polymorphic region (5-HTTLPR) in predicting depression, but it has rarely considered genetic influences on stress sensitization processes, whereby early adversities (EA) increase depressive reactivity to proximal stressors later in life. The current study tested a gene-environment-environment interaction (G × E × E; specifically, gene-EA-proximal stress interaction) model of depression in a 20-year longitudinal study. Participants were assessed prospectively for EA up to age 5 and recent chronic stress and depressive symptoms at age 20 and genotyped for CRHR1 single nucleotide polymorphism rs110402 and 5-HTTLPR. EA predicted stronger associations between recent chronic stress and depression, and the effect was moderated by genes. CRHR1 A alleles and 5-HTTLPR short alleles were associated with greater stress sensitization (i.e., greater depressive reactivity to chronic stress for those also exposed to high levels of EA). The results are consistent with the notion that EA exposure results in neurobiological and cognitive-emotional consequences (e.g., altered hypothalamic-pituitary-adrenal axis functioning), leading to emotional distress in the face of recent stressors among those with certain genetic characteristics, although further research is needed to explore explanatory mechanisms.

Transdiagnostic and disorder-specific models of intergenerational transmission of internalizing pathology

BACKGROUND Numerous studies have supported an association between maternal depression and child psychiatric outcomes, but few have controlled for the confounding effects of both maternal and offspring co-morbidity. Thus, it remains unclear whether the correspondence between maternal and offspring depressive and anxiety disorders is better explained by associations between shared features of maternal and offspring internalizing disorders or by specific effects exerted by unique aspects of individual disorders. METHOD Pairs of mothers and offspring overselected for maternal depression (n = 815) were assessed at offspring age 15 years for anxiety and depressive disorders; 705 completed a follow-up at offspring age 20 years. For both mothers and offspring, structural equation modeling was used to distinguish transdiagnostic internalizing pathology--representing the overlap among all depressive and anxiety disorders--from diagnosis-specific forms of pathology. To discriminate between general versus specific pathways of intergenerational transmission of psychopathology, we examined (a) the general association between the maternal and offspring internalizing factors and (b) the correlations between maternal and offspring diagnosis-specific pathology for each disorder. RESULTS For mothers and offspring, a unidimensional latent variable model provided the best fit to the correlations among depressive and anxiety disorders. The maternal transdiagnostic internalizing factor strongly predicted the corresponding factor among offspring. In addition, the unique component of post-traumatic stress disorder among offspring was significantly related to the analogous unique component among mothers, but specific components of other maternal disorders, including depression, did not predict corresponding offspring pathology. CONCLUSIONS Results suggest that intergenerational transmission of internalizing disorders is largely non-specific.

Daily stress reactivity and serotonin transporter gene (5-HTTLPR) variation: internalizing responses to everyday stress as a possible transdiagnostic phenotype

BackgroundRecent studies examining the interaction between the 5-HTTLPR locus in the serotonin transporter gene and life stress in predicting depression have yielded equivocal results, leading some researchers to question whether 5-HTTLPR variation indeed regulates depressive responses to stress. Two possible sources of inconsistent data in this literature are imprecise stress assessment methodologies and a restricted focus on depression phenotypes as the outcome of interest, as opposed to transdiagnostic emotional symptoms such as internalizing and externalizing dimensions. The present study aimed to address these critical limitations in prior research by examining how 5-HTTLPR acts in concert with idiographically assessed daily life stress to predict transdiagnostic emotional outcomes.ResultsOne hundred and four healthy young adults genotyped for 5-HTTLPR reported on their life stress exposure and internalizing and externalizing experiences for 14 consecutive days. As hypothesized, daily stress levels were associated with severity of internalizing symptoms, but only for 5-HTTLPR S allele carriers. Additional analyses revealed that these interactive effects of 5-HTTLPR and daily life stress on internalizing symptoms extended to both the distress and fear subdomains of internalizing symptoms.ConclusionsConsidered together, these results support the validity of the 5-HTTLPR stress sensitivity hypothesis and suggest for the first time that variation at 5-HTTLPR moderates the effects of daily life stress on broadband symptom profiles.

Dysfunctional Attitudes and Affective Responses to Daily Stressors: Separating Cognitive, Genetic, and Clinical Influences on Stress Reactivity

Despite decades of research examining diathesis-stress models of emotional disorders, it remains unclear whether dysfunctional attitudes interact with stressful experiences to shape affect on a daily basis and, if so, how clinical and genetic factors influence these associations. To address these issues, we conducted a multi-level daily diary study that examined how dysfunctional attitudes and stressful events relate to daily fluctuations in negative and positive affect in 104 young adults. Given evidence that clinical and genetic factors underlie stress sensitivity, we also examined how daily affect is influenced by internalizing and externalizing symptoms and brain-derived neurotrophic factor (BDNF) genotype, which have been shown to influence neural, endocrine, and affective responses to stress. In multivariate models, internalizing symptoms and BDNF Val66Met genotype independently predicted heightened negative affect on stressful days, but dysfunctional attitudes did not. Specifically, the BDNF Met allele and elevated baseline internalizing symptomatology predicted greater increases in negative affect in stressful circumstances. These data are the first to demonstrate that BDNF genotype and stress are jointly associated with daily fluctuations in negative affect, and they challenge the assumption that maladaptive beliefs play a strong independent role in determining affective responses to everyday stressors. The results may thus inform the development of new multi-level theories of psychopathology and guide future research on predictors of affective lability.

ADOLESCENT PRECURSORS OF ADULT BORDERLINE PERSONALITY PATHOLOGY IN A HIGH-RISK COMMUNITY SAMPLE

Longitudinal studies of the exact environmental conditions and personal attributes contributing to the development of borderline personality disorder (BPD) are rare. Furthermore, existing research typically examines risk factors in isolation, limiting our knowledge of the relative effect sizes of different risk factors and how they act in concert to bring about borderline personality pathology. The present study investigated the prospective effects of diverse acute and chronic stressors, proband psychopathology, and maternal psychopathology on BPD features in a high-risk community sample (N = 700) of youth followed from mid-adolescence to young adulthood. Multivariate analyses revealed significant effects of maternal externalizing disorder history, offspring internalizing disorder history, family stressors, and school-related stressors on BPD risk. Contrary to expectations, no interactions between chronically stressful environmental conditions and personal characteristics in predicting borderline personality features were detected. Implications of these findings for etiological theories of BPD and early screening efforts are discussed.

Cross-Domain Assessment of Distress Intolerance: Associations With Borderline Personality Disorder Features

Distress tolerance (DT) is central to major etiological theories of, and popular treatments for, borderline personality disorder (PD), but empirical evidence for the connection between DT and borderline PD is inconclusive. Such inconsistency is partly due to limited concordance across DT indices from different measurement domains (e.g., behavioral, physiological). In a student sample (N = 267), we assessed subjective perceptions of DT capabilities, task performance on a distressing laboratory challenge, and borderline pathology. Subjective and behavioral indices of DT were largely unrelated. Further, borderline PD features were moderately associated with self-perceived DT (r = -.53); in contrast, they were weakly related to performance on the DT task (r = -.09). We conclude that there is mixed evidence for an association between borderline pathology and DT. Further, we propose a systematic approach to examining the construct validity of DT in multimethod, multimeasure research that might resolve the equivocal results from prior work.

Borderline personality disorder is equally trait-like and state-like over ten years in adult psychiatric patients.

Borderline personality disorder (PD) has historically been cast as an unabating condition. Longitudinal data, however, support a more variable time course marked by remission and relapse. In the present study, we tested the possibility that borderline PD has both stable (i.e., consistently present across time and situation, as modern diagnostic systems stipulate) and dynamic (i.e., episodic and situational) elements. Participants were 668 patients from the Collaborative Longitudinal Personality Disorders Study who were administered semistructured diagnostic interviews 5 times over a decade. Trait–state-occasion modeling dissected borderline pathology into time-invariant (i.e., trait) and time-varying (i.e., state) components. Contradicting traditional views of PD intransigence, less than half of borderline PD variability (approximately 45%) was time-invariant (i.e., perfectly stable) over the study timeframe. Furthermore, we found that the time-invariant component of borderline pathology, which we termed borderline proneness, was very closely related (r = .81) to a previously validated Five Factor Model trait composite of borderline features. Moreover, the trait versus state components showed a clear pattern of discriminant validity in relation to several putative causal agents for borderline PD (i.e., environmental pathogens, temperament dimensions). We conclude that borderline pathology contains a stable core and sizable situational components, and that both elements relate systematically to normative personality dimensions and known risk factors. These findings have key implications for etiological research, prognosis, and treatment for borderline PD.

Optimierung expositionsbasierter Therapie@@@Maximizing exposure therapy: Ein Ansatz des inhibitorischen Lernens@@@An inhibitory learning approach

ZusammenfassungExposition ist eine wirksame Behandlung bei Angststörungen, jedoch zeigt eine substanzielle Anzahl von Klienten keine signifikante Symptomreduktion oder ein Wiederkehren der Angst. Es wird angenommen, dass ängstliche Personen Defizite in grundlegenden Mechanismen der Expositionstherapie, wie dem inhibitorischen Lernen, aufweisen. Ein gezieltes Ansprechen dieser Defizite könnte demnach die Wirksamkeit von Exposition optimieren. Allerdings fehlen bisher Vorschläge zur konkreten Umsetzung in der Praxis. Dieser Beitrag verdeutlicht anhand verschiedener Strategien, wie das Modell zur Optimierung der Behandlung von Angststörungen praktisch umsetzbar ist. Die vorgeschlagenen Strategien unterscheiden sich hierbei von einem reinen habituationsbasierten Ansatz oder kognitiven Ansätzen zur Widerlegung von Überzeugungen. Die Strategien umfassen: 1) das Widerlegen angstbezogener Erwartungen, 2) vertiefte Extinktion, 3) Extinktion mit gelegentlicher Verstärkung, 4) Entfernen von Sicherheitssignalen, 5) Variabilität, 6) Erinnerungsreize, 7) multiple Kontexte und 8) affektives Labeling. Durch Fallbeispiele wird die Anwendung dieser Strategien bei verschiedenen Angststörungen illustriert.AbstractExposure is an effective approach for treating anxiety disorders, although a substantial number of individuals fail to benefit or experience a return of fear. Research results suggest that anxious individuals show deficits in the mechanisms underlying exposure therapy, such as inhibitory learning. Targeting these processes may help improve the efficacy of exposure; however, there has been little discussion of how to implement this model in clinical practice. The primary aim of this paper is to provide examples to clinicians for how to apply this model to optimize exposure therapy, in ways that distinguish it from a fear habituation approach and a belief disconfirmation approach. Optimization strategies include (1) expectancy violation, (2) deepened extinction, (3) occasional reinforced extinction, (4) removal of safety signals, (5) variability, (6) retrieval cues, (7) multiple contexts and (8) affect labeling. Case studies illustrate methods of applying these techniques with a variety of anxiety disorders.